Numerous polymer-based medical devices have been developed for the delivery of therapeutic agents to the body. In accordance with some typical delivery strategies, a therapeutic agent is provided within a polymeric carrier layer and/or beneath a polymeric barrier layer that is associated with a medical device. Once the medical device is placed at the desired location within a patient, the therapeutic agent is released from the medical device at a rate that is dependent upon the nature of the polymeric carrier and/or barrier layer.
Materials which are suitable for use in making implantable or insertable medical devices typically exhibit one or more of the qualities of exceptional biocompatibility, extrudability, elasticity, moldability, good fiber forming properties, tensile strength, durability, and the like. Moreover, the physical and chemical characteristics of the device materials can play an important role in determining the final release rate of the therapeutic agent. Although controlled release of a therapeutic agent by means of polymeric materials has existed in various forms for many years, there is a continuing need for improved and more precise drug delivery systems, particularly for those materials whose release rate characteristics of an incorporated therapeutic agent may be readily modulated depending on the required need.
Thus, when such biocompatible materials are utilized as drug delivery systems, it is important to select materials that possess good drug release characteristics and also that are robust enough to withstand the rigors of standard medical device manufacturing processing such as sterilization.
As a specific example, block copolymers of polyisobutylene and polystyrene, for example, polystyrene-polyisobutylene-polystyrene triblock copolymers (SIBS copolymers), which are described in U.S. Pat. No. 6,545,097 to Pinchuk et al., which is hereby incorporated by reference in its entirety, have proven valuable as release polymers in implantable or insertable drug-releasing medical devices. As described in Pinchuk et al., the release profile characteristics of therapeutic agents such as paclitaxel from SIBS copolymer systems demonstrate that these copolymers are effective drug delivery systems for providing therapeutic agents to sites in vivo.
These copolymers are particularly useful for medical device applications because of their excellent mechanical characteristics, biostability and biocompatibility, particularly within the vasculature. The SIBS copolymers exhibit high tensile strength, which frequently ranges from 2,000 to 4,000 psi or more, and resist cracking and other forms of degradation under typical in vivo conditions. Biocompatibility, including vascular compatibility, of these materials has been demonstrated by their tendency to provoke minimal adverse tissue reactions (e.g., as measured by reduced macrophage activity). In addition, these polymers are generally hemocompatible as demonstrated by their ability to minimize thrombotic occlusion of small vessels when applied as a coating on coronary stents.
In addition, these polymers possess many interesting physical and chemical properties sought after in medical devices, due to the combination of the polyisobutylene and polystyrene blocks. Polyisobutylene has a low glass transition temperature (Tg) and is soft and elastomeric at room (and body) temperature. Polystyrene, on the other hand, has a much higher Tg and is thus hard at these temperatures. Polystyrene is also thermoplastic in nature, opening up a wide range of processing capabilities. Depending upon the relative amounts of polystyrene and polyisobutylene, the resulting copolymer can be formulated to have a range of hardness, for example, from as soft as about Shore 10A to as hard as about Shore 100D.
Despite these desirable qualities, there is a continuing need for improved materials for use as drug delivery systems. For example, SIBS copolymers are synthesized by a living cationic polymerization process, a complex process that requires stringent reaction conditions and low temperatures. Ionic (cationic and anionic) polymerizations typically require reaction conditions free of moisture, oxygen, as well as impurities. To date, only a limited number of monomers, such as isobutylene, have been polymerized by a living cationic polymerization process, thus restricting the ability to vary the chemical composition of polymers and copolymers produced by this process. Further, the experimental rigor generally involved in ionic polymerizations is often too costly for industrial use and free radical routes are preferred. In addition, homopolymers and copolymers containing polyisobutylene such as a SIBS copolymer may be more susceptible to radiation effects and undergo undesirable changes to its mechanical and drug-eluting properties, especially at the radiation levels typically used for medical device sterilization (e.g., about 1.0 to 5.0 Mrad, or even higher).
Hence, it would be advantageous to provide polymers having various properties that are analogous to those of SIBS copolymers (e.g., drug release characteristics, biostability, biocompatibility, etc.), but which also exhibit potentially improved immunity to radiation-based changes in polymer properties and can be synthesized using a wider array of monomer materials. In addition, it would be advantageous to provide blended copolymers containing SIBS with all of its desirable traits, with other polymer materials that provide other important physical or mechanical properties such as radiation-resistance, cross-linking abilities, and drug release characteristics.